Reproductive and transgenerational toxicity of bisphenol S exposure in pregnant rats: Insights into hormonal imbalance and steroid biosynthesis pathway disruption.

Bisphenol S (BPS) is an alternative chemical to bisphenol A commonly used in food packaging materials. It raises concerns due to potential adverse effects on human health. However, limited evidence exists regarding reproductive toxicity from BPS exposure, and the mechanism of associated transgenerational toxicity remains unclear. In this study, pregnant SD rats were exposed to two different doses of BPS (0.05 or 20 mg/kg) from GD6 to PND21. The objective was to investigate reproductive and transmissible toxicity induced by BPS, explore endocrine effects, and uncover potential underlying mechanisms in rats. Perinatal exposure to BPS in the F0 generation significantly decreased the rate of body weight, ovarian organ coefficient, and growth and development of the F1 generation. Notably, these changes included abnormal increases in body weight and length, estrous cycle disruption, and embryonic dysplasia in F1. 4D-DIA proteomic and PRM analyses revealed that exposure to 20 mg/kg group significantly altered the expression of proteins, such as Lhcgr and Akr1c3, within the steroid biosynthetic pathway. This led to elevated levels of FSH and LH in the blood. The hypothalamic-pituitary-ovarian (HPO) axis, responsible for promoting fertility through the cyclic secretion of gonadotropins and steroid hormones, was affected. RT-qPCR and Western blot results demonstrated that the expression of GnRH in the hypothalamus was decreased, the GnRHR in the pituitary gland was decreased, and the expression of FSHß and LHß in the pituitary gland was increased. Overall, BPS exposure disrupts the HPO axis, hormone levels, and steroid biosynthesis in the ovaries, affecting offspring development and fertility. This study provides new insights into the potential effects of BPS exposure on the reproductive function of the body and its relevant mechanisms of action.

Cardiac echinococcosis secondary to hepatic echinococcosis: a rare case report.

Cystic echinococcosis (CE) is a zoonotic parasitic infection, which is very rare in developed countries. It can affect all internal organs, while cardiac echinococcosis is extremely rare, especially in children. Slowly enlarging hydatid cyst usually remains asymptomatic until the size or space occupying effects the involved organ and induces symptoms. The progression of cardiac echinococcosis can be very hidden, and the symptoms are similar to that of other cardiovascular diseases, which raises the difficulty in accurate diagnosis. We present a 13-year-old young girl with a history of hepatic echinococcosis who developed a huge cardiac hydatid cyst, but her symptoms were not specific, while the physical tests and biochemical examinations were unremarkable. Her residential area in Tibet and previous medical history of hepatic echinococcosis gave us clues in the diagnosis of cardiac echinococcosis. Combined with computed tomography (CT) and magnetic resonance imaging (MRI), the cardiac echinococcosis was finally confirmed, and the cardiac symptoms were relieved after surgical removal of the cardiac hydatid cyst. This is the first report of children's cardiac echinococcosis secondary to hepatic echinococcosis, and it remarks on the importance of rapid consideration of cardiac echinococcosis even if no remarkable symptoms or indexes are present. Moreover, the combination of previous history and imaging techniques are indispensable for obtaining a definite diagnosis.

Cascade Tumor Therapy Platform for Sensitized Chemotherapy and Penetration Enhanced Photothermal Therapy.

As a stand-alone therapy strategy may not be sufficient for effective cancer treatment and a combination of chemotherapy with other therapies is a main trend in cancer treatment. A combination of chemotherapy and photothermal therapy (PTT) is reported here to achieve the goal of cascade multistage cancer treatment. A thermally responsive amphiphilic copolymer is designed and then a CuS nanoparticles (NPs)-based carbon monoxide (CO) photoinduced release system and doxorubicin (Dox) are encapsulated to construct the nanomedicine. The large-sized nanomedicine can accumulate in tumors after long circulation in vivo and will generate heat to act as a photothermal therapeutic agent by near infrared (NIR) light. Moreover, synergically release of CO and Dox is achieved and acted as a sensitized chemotherapeutic agent. The combination of PTT and chemotherapy sensitization can effectively eliminate active tumor cells in the periphery of the tumor. CuS NPs are also released after the degradation of nanomedicine and small-sized CuS NPs possess better tumor penetration and achieve penetration-enhanced PTT by further NIR irradiation, thereby effectively eliminating tumor cells inside solid tumors. Hence, cascade multistage cancer treatment of "combined PTT and chemotherapy sensitization"-"penetration-enhanced PTT" is achieved, and tumor cells are comprehensively and effectively eliminated.

Tumor Cell Distinguishable Nanomedicine Integrating Chemotherapeutic Sensitization and Protection.

Theoretically, with a high enough drug dosage, cancer cells could be eliminated. However, the dosages that can be administered are limited by the therapeutic efficacy and side effects of the given drug. Herein, a nanomedicine integrating chemotherapeutic sensitization and protection was developed to relieve the limitation of administration dosage and to improve the efficacy of chemotherapy. The nanomedicine was endowed with the function of synergistically controlled release of CO and drugs under near-infrared (NIR) light irradiation. CO photo-induced release system (COPIRS) was synthesized by constructing an electron excitation-electron transfer group-electron-induced CO release structure and was used as the hydrophobic part, and then hydrophilic polymer (polyethylene glycol; PEG) was introduced by a thermal-responsive groups (DA group), forming a near-infrared-induced burst-release nanocarrier. In vitro and in vivo experiments showed that the nanomedicine can distinguish between tumor and normal cells and regulates the resistance of these different cells through the controlled release of carbonic oxide (CO), simultaneously enhancing the efficacy of chemotherapy drugs on tumor cells and chemotherapeutic protection on normal cells. This strategy could solve the current limitations on dosages due to toxicity and provide a solution for tumor cure by chemotherapy.

A Rapid Dual-Responsive Releasing Nano-Carrier by Decomposing the Copolymer and Reversing the Core Dissolution.

The accumulation of nanotechnology-based drugs has been realized in various ways. However, the concentration of drugs encapsulated by nanomaterials is not equal to the concentration of effective drugs; often, the drugs become effective only when they are released from the nanomaterials as free drugs. This means only when the drugs are rapidly released after the accumulated drug-encapsulating nanomaterials can they truly achieve the purpose of increasing the concentration of drugs in the tumor. Therefore, we herein report a dual-response nano-carrier of glutathione and acid to achieve the rapid release of encapsulated drug and increase the effective drug concentration in the tumor. The nano-carrier was constructed using a dual-responsive amphiphilic copolymer, composed of polyethylene glycol and hydrophobic acetylated dextran and connected by a disulfide bond. In the tumor microenvironment, disulfide bonds could be biodegraded by glutathione that is overexpressed in the tumor, exposing the core of nano-carrier composed of acetylated dextran. Then the acidic environment would induce the deacetylation of acetylated dextran into water-soluble dextran. In this way, the nano-carrier will degrade quickly, realizing the purpose of rapid drug release. The results showed that the drug release rate of dual-responsive nano-carrier was much higher than that of glutathione or acid-responsive nano-carrier alone. Furthermore, both in vitro and in vivo experiments confirmed that dual-responsive nano-carrier possessed more efficient anti-tumor effects. Therefore, we believe that dual-responsive nano-carriers have better clinical application prospects.

Sensitive fluorescence and visual detection of organophosphorus pesticides with a Ru(bpy)32+-ZIF-90-MnO2 sensing platform.

Fluorescence sensing organophosphorus pesticides (OPs) is of great importance for both food safety and global environment; however, the reported fluorescent probes are usually directly exposed to the external environment, resulting in premature leakage or photobleaching and thus limiting their photostability and assay sensitivity. In this work, a fluorescent sensing platform consisting of a novel luminescent metal-organic framework (Ru(bpy)32+-ZIF-90) and manganese dioxide nanosheets (MnO2 NSs) was prepared for sensing OPs. Due to the protection and improvement in the fluorescence of Ru(bpy)32+ by ZIF-90, the Ru(bpy)32+-ZIF-90 probe displayed remarkable photostability and high stability in water. By virtue of the high stability of Ru(bpy)32+-ZIF-90, as well as the outstanding fluorescence quenching and notable recognition ability of the MnO2 NSs, this sensing platform provided excellent detection capability for parathion-methyl, with a wide concentration range of 0.050-60 ng mL-1 and a low detection limit of 0.037 ng mL-1. Additionally, the system exhibited a visual color change with the concentration of the OPs under sunlight. Moreover, satisfactory recoveries ranging from 93.3% to 103.6% were obtained for the real samples. The results indicated that the Ru(bpy)32+-ZIF-90-MnO2-based OP sensing platform is promising for applications in food safety and environmental monitoring.

Associations between TAB2 Gene Polymorphisms and Epithelial Ovarian Cancer in a Chinese Population.

BACKGROUND: Epithelial ovarian cancer (EOC) is highly lethal worldwide. Factors involved in the inflammation and hormone-associated signaling pathway play vital roles in EOC carcinogenesis. The transforming growth factor-ß- (TGF-ß-) activated kinase 1 (MAP3K7) binding protein 2 (TAB2), mediating convergence of inflammatory and estrogen, may be implicated in EOC. The present study is aimed at exploring the association between the TAB2 gene polymorphisms and EOC. METHODS: Three single nucleotide polymorphisms (SNPs) (rs237028, rs521845, and rs652921) of TAB2 were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 221 patients and 252 healthy controls. Associations between SNPs and clinical characteristics were performed either with the χ 2 test or with Fisher's exact test. The Kaplan-Meier method and Cox proportional hazard models were used to detect associations between genotypes and overall survival. RESULTS: The rs237028 polymorphism was significantly associated with an increased risk of EOC with an allelic genetic model (A vs. G; OR = 1.45; 95%CI = 1.07-1.96; P = 0.016), dominant genetic model (AA vs. AG-GG; OR = 1.66; CI 1.14-2.41; P = 0.008), and overdominant genetic model (AA-GG vs. AG; OR = 1.60; CI 1.08-2.36; P = 0.017). However, no significant association was observed between rs237028 polymorphism and overall survival. CONCLUSIONS: Our study indicated that the rs237028 polymorphism in the TAB2 gene was associated with EOC susceptibility and the TAB2 gene might contribute to the initiation of EOC.

Oridonin overcomes the gemcitabine resistant PANC-1/Gem cells by regulating GST pi and LRP/1 ERK/JNK signalling.

Background: Chemotherapy remains a primary treatment method for advanced pancreatic cancer. However, chemotherapy resistance can influence the therapeutic effect of pancreatic cancer. The resistance mechanism of chemotherapeutic agents such as gemcitabine, which is an agent typically used to treat pancreatic cancer, is complicated and can be influenced by genes and the environment. Oridonin is a tetracyclic diterpenoid compound extracted from the traditional Chinese herb Rabdosia labtea. Oridonin may overcome drug resistance in pancreatic cancer, but researching pancreatic cancer drug resistance of chemotherapy by oridonin is not completely understood. Purpose: The present study aimed to assess the impact of oridonin on multidrug resistance proteins, apoptosis-associated proteins and energy metabolism in gemcitabine-resistant PANC-1 (PANC-1/Gem) pancreatic cancer cells. Methods: Gemcitabine resistance in PANC-1/Gem cells was induced using a concentration gradient of gemcitabine. Cell Counting Kit-8 assays were used to detect the impact of gemcitabine and oridonin on the proliferation of PANC-1 and PANC-1/Gem cells. Western blot analysis and immunofluorescence were used to detect the expression of multidrug resistance proteins, apoptosis-associated proteins and low-density lipoprotein receptor protein 1 (LRP1) proteins in PANC-1/Gem cells. The effects of gemcitabine and oridonin on PANC-1/Gem cells apoptosis were detected using flow cytometry. Animal xenograft tumor assays were used to detect the effect of gemcitabine and oridonin on pancreatic cancer in vivo. Furthermore, the ATP Assay kit was used to determine the effects of gemcitabine and oridonin on ATP levels in PANC-1/Gem cells. Immunofluorescence assays were used to detect the effects of gemcitabine and oridonin on the expression of low-density lipoprotein receptor protein 1 (LRP1) in PANC-1/Gem cells. In addition, LRP1 expression was knocked down in PANC-1/Gem cells via lentiviral vector-mediated RNA silencing. Clone formation assays and Western blot analysis were used to detect the effect of LRP1 knockdown on the proliferation of PANC-1/Gem cells. Results: The present results demonstrate that oridonin overcomes PANC-1/Gem cells gemcitabine reistance by regulating GST pi and LRP1/ERK/JNK signaling. Conclusion: In conclusion, the present study indicated that oridonin could overcome gemcitabine resistance in PANC-1/Gem cells by regulating GST pi and LRP1/ ERK/JNK signaling, inducing cell apoptosis. Therefore, oridonin with gemcitabine may be a promising preoperative treatment for patients who suffer from pancreatic cancer.

Oridonin inhibition and miR­200b­3p/ZEB1 axis in human pancreatic cancer.

The relationship among oridonin, miR-200b-3p and pancreatic cancer on epithelial-to-mesenchymal transition (EMT) was investigated for the molecular mechanism or signaling pathways on the migration in pancreatic cancer. BxPC-3 and PANC-1 cells were cultivated and the IC50 of oridonin in BxPC-3 and PANC-1 cells were obtained by the CCK-8 array. The expression of miR­200b-3p was verified by using real-time PCR and its target gene was predicted. BxPC-3 and PANC-1 cells were treated with oridonin or transfected by miR-200b-3p, those cells were used for western blot assay, Transwell assay, ELISA, immunofluorescence staining, tumorigenesis assay in nude mice and immunohistochemical assay to verify the effects of oridonin or miR-200b-3p on pancreatic cancer. We found that oridonin inhibited the proliferation of BxPC-3 and PANC-1 cells in a dose-dependent manner. miR-200b-3p was downregulated by oridonin in BxPC-3 and PANC-1 cells. ZEB1 was a target gene for miR-200b-3p. Oridonin or overexpression of miR­200b-3p can inhibit the cell migration in BxPC-3 and PANC-1 cells. miR-200b-3p can inhibit the EMT and oridonin can inhibit the expression of ZEB1, N-cadherin and fibronectin but not increase the expression of E-cadherin, while the cell adhesion molecules ICAM-1 and VCAM-1 were decreased by oridonin in BxPC-3 and PANC-1 cells and the cytoskeleton was altered by oridonin in PANC-1 cells compared with the control. In summary, the results demonstrate that miR­200b-3p was able to inhibit the EMT of human pancreatic cancer in vivo and in vitro by targeted ZEB1. In vitro, oridonin had a certain effect on the migration in BxPC-3 and PANC-1 cells, but not though type III EMT by miR-200-3p/ZEB1 axis, and may be related to type â…¡ EMT, tumor microenvironment or altering the cytoskeleton. In vivo, oridonin inhibited the cancer migration in the nude mouse model though inhibiting EMT.

Liberation of SARS-CoV main protease from the viral polyprotein: N-terminal autocleavage does not depend on the mature dimerization mode.

The main protease (M(pro)) plays a vital role in proteolytic processing of the polyproteins in the replicative cycle of SARS coronavirus (SARS-CoV). Dimerization of this enzyme has been shown to be indispensable for trans-cleavage activity. However, the auto-processing mechanism of M(pro), i.e. its own release from the polyproteins through autocleavage, remains unclear. This study elucidates the relationship between the N-terminal autocleavage activity and the dimerization of "immature" M(pro). Three residues (Arg4, Glu290, and Arg298), which contribute to the active dimer conformation of mature M(pro), are selected for mutational analyses. Surprisingly, all three mutants still perform N-terminal autocleavage, while the dimerization of mature protease and trans-cleavage activity following auto-processing are completely inhibited by the E290R and R298E mutations and partially so by the R4E mutation. Furthermore, the mature E290R mutant can resume N-terminal autocleavage activity when mixed with the "immature" C145A/E290R double mutant whereas its trans-cleavage activity remains absent. Therefore, the N-terminal auto-processing of M(pro) appears to require only two "immature" monomers approaching one another to form an "intermediate" dimer structure and does not strictly depend on the active dimer conformation existing in mature protease. In conclusion, an auto-release model of M(pro) from the polyproteins is proposed, which will help understand the auto-processing mechanism and the difference between the autocleavage and trans-cleavage proteolytic activities of SARS-CoV M(pro).